| 1. |
- Emtenäs, Hans, et al.
(författare)
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An Enantioselective Ketene-Imine Cycloaddition Method for Synthesis of Substituted Ring-Fused 2-Pyridinones
- 2001
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Ingår i: The Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 66:20, s. 6756-61
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Tidskriftsartikel (refereegranskat)abstract
- Previously, a method for the stereoselective synthesis of -lactams, starting from 2H-2-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-2-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 78 C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 64 C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different 2-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.
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| 2. |
- Emtenäs, Hans, et al.
(författare)
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Design and Parallel Solid Phase Synthesis of Ring Fused 2-Pyridinones that Target Pilus Biogenesis in Pathogenic Bacteria
- 2002
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Ingår i: Journal of Combinatorial Chemistry. - : American Chemical Society (ACS). - 1520-4766 .- 1520-4774. ; 4, s. 630-639
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Tidskriftsartikel (refereegranskat)abstract
- A new method for the solid-phase synthesis of enantiomerically enriched highly substituted ring-fused 2-pyridinones 13 has been developed. The synthesis mediates introduction of substituents at two positions in the 2-pyridinone ring in a diverse manner and is suitable for parallel synthesis. 19F NMR spectroscopy was used as a tool to monitor each of the five steps in the reaction sequence. The optimized conditions thus obtained were then used to prepare a library of 20 2-pyridinones with high yields. The library members were chosen from a statistical multivariate design to ensure diversity and reliable data for structure−activity relationships. Screening of the library against the bacterial periplasmic chaperone PapD was performed using surface plasmon resonance. Three new 2-pyridinones with a higher affinity for the chaperone PapD than the previous best 13{10,1} were found, and important structural features could be deduced.
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| 3. |
- Emtenäs, Hans, et al.
(författare)
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Efficient Microwave Assisted Synthesis of Optically Active Bicyclic 2-Pyridinones via Δ2-Thiazolines
- 2003
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Ingår i: Molecular diversity. - : Springer Netherlands. - 1381-1991 .- 1573-501X. ; :2-4, s. 165-169
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Tidskriftsartikel (refereegranskat)abstract
- A new efficient synthesis of optically active bicyclic 2-pyridiones has been developed using microwave irradiation. The synthesis is a two-step procedure via 2-thiazolines, which only requires a 3 + 2 min reaction time compared to 2 days when using conventional heating. The optimized conditions proved to be suitable for the synthesis of a small library in excellent yields and with limited racemizations.
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| 4. |
- Emtenäs, Hans, et al.
(författare)
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Stereoselective synthesis of optically active bicyclic -lactam carboxylic acids that target pilus biogenesis in pathogenic bacteria
- 2003
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Ingår i: Organic & Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 1, s. 1308-14
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Tidskriftsartikel (refereegranskat)abstract
- Optically active bicyclic -lactams were synthesized, starting from 2-H-2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the -lactam framework were investigated. A rapid CsOH saponification of the -lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicyclic -lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic -lactam carboxylic acids 7a–g and aldehydes 4a–d were screened for their affinity to the bacterial periplasmic chaperone PapD using a surface plasmon resonance technique. -Lactams substituted with large acyl substituents showed better binding to the chaperone than the native C-terminal peptide PapG 8, demonstrating that bicyclic -lactams constitute a new class of potential bacterial chaperone inhibitors.
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| 5. |
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| 6. |
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| 7. |
- Emtenäs, Hans, 1972-
(författare)
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Synthesis and biological evaluation of Bicyclic β-Lactams and 2-Pyridinones : Pilicides Targeting Pilus Biogenesis in Pathogenic Bacteria
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- New methods have been developed for the synthesis of bicyclic β-lactams and 2-pyridinones by combining acyl Meldrum’s acids and Δ2-thiazolines. The 2-pyridinones were synthesised both in solution using conventional heating or microwave assisted heating as well as by solid supported chemistry. The compounds (pilicides) were designed to interfere with the assembly of pili in uropathogenic E. coli by inhibiting the periplasmic chaperones. The affinity of the pilicides to the chaperones was investigated with surface plasmon resonance technique (Biacore) and with relaxation-edited 1H NMR spectroscopy experiments. Finally, the pilicides were investigated for their ability to inhibit pili formation in uropathogenic E. coli in a hemagglutination assay, where members of the 2-pyridinone family proved to be able to cause depiliation.
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| 8. |
- Hedenström, Mattias, et al.
(författare)
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NMR studies of interactions between periplasmic chaperones from uropathogenic E-coli and pilicides that interfere with chaperone function and pilus assembly
- 2005
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Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 3:23, s. 4193-4200
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Tidskriftsartikel (refereegranskat)abstract
- Adherence of uropathogenic Escherichia coli to host tissue is mediated by pili, which are hair-like protein structures extending from the outer cell membrane of the bacterium. The chaperones FimC and PapD are key components in pilus assembly since they catalyse folding of subunits that are incorporated in type 1 and P pili, respectively, and also transport the subunits across the periplasmic space. Recently, compounds that inhibit pilus biogenesis and interfere with chaperone-subunit interactions have been discovered and termed pilicides. In this paper NMR spectroscopy was used to study the interaction of different pilicides with PapD and FimC in order to gain structural knowledge that would explain the effect that some pilicides have on pilus assembly. First relaxation-edited NMR experiments revealed that the pilicides bound to the PapD chaperone with mM affinity. Then the pilicide-chaperone interaction surface was investigated through chemical shift mapping using N-15-labelled FimC. Principal component analysis performed on the chemical shift perturbation data revealed the presence of three binding sites on the surface of FimC, which interacted with three different classes of pilicides. Analysis of structure-activity relationships suggested that pilicides reduce pilus assembly in E. coli either by binding in the cleft of the chaperone, or by influencing the orientation of the flexible F1-G1 loop, both of which are part of the surface by which the chaperone forms complexes with pilus subunits. It is suggested that binding to either of these sites interferes with folding of the pilus subunits, which occurs during formation of the chaperone-subunit complexes. In addition, pilicides that influence the F1-G1 loop also appear to reduce pilus formation by their ability to dissociate chaperone-subunit complexes.
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| 9. |
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| 10. |
- Pemberton, Nils, et al.
(författare)
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Cycloaddition of 2-thiazolines and acyl ketenes under acidic conditions results in bicyclic 1,3-oxazinones and not 6-acylpenams as earlier reported
- 2005
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Ingår i: Organic Letters. - Washington, D.C. : American Chemical Society. - 1523-7060 .- 1523-7052. ; 7:6, s. 1019-1021
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Tidskriftsartikel (refereegranskat)abstract
- Optically active 2-thiazolines 4 were previously reported to react with acyl Meldrum's acid derivatives 5 under acidic conditions (HCl (g) in benzene) to stereoselectively give 6-acylpenams 1. Recently we have discovered that the structure elucidation of these compounds was incorrect. Thus, we report new data showing that instead of acyl -lactams, the optically active isomers 3R,9R-1,3-oxazinones 3a-g are obtained stereoselectively in 38-93% yields.
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